The first decision to make is where on the axial skeleton the developing limb buds will be positioned. Then developing limb, like the body itself, has to generate 3 different axes anterior/posterior, dorsal/ventral, and proximal/distal.
Forelimb Axes (stage 14)
Early transplantation experiments identified 2 specific regions within the developing limb buds that were involved in establishing patterns within the limb. The zone of polarizing activity (ZPA) is a mesodermal region within the posterior margin of the limbbud. The apical ectodermal ridge (AER) is a narrow ridge of ectoderm at the tip of the limb bud.
The patterning signal secreted from the ZPA is sonic hedgehog (SHH).
Limb Initiation and Positioning on the axial skeleton.
The zone of polarizing activity (ZPA) is a mesenchymal region within the posterior margin of the limbbud which patterns the anterior/posterior axis of the limb. The most obvious pattern seen from this signal is the organization of the digits.
The proximo/distal axis appears to be regulated by at least 3 signaling steps.
Mesenchyme within the limb bud may be also patterned by adjacent structures such as somites (dorsal signal) or somatopleure mesoderm (ventral signal). Overlying ectoderm can then be patterned by this specified mesenchyme, which then itself is the source of a continued dorso/ventral signal.
Please note that these notes only relate to the Anat 3311 Course. This section is not completely available, as I have been unable to transfer all my Lecture notes and research material in time for the deadline. This will be available in later versions. Early Development Lecture
Simple pictures illustrating the early events of fertilization.
Figures and text relating to early events of spinal cord formation.
Text relating to the molecular events of sex determination in the embryo.
Polarity ConceptsA short comparison of establishing positional information in embryos.
AntennapediaThe fly mutation that opened the field of Hox Genes and the conservation of pattern formation control mechanisms between species in embryonic development.
Recent Limb Development Reviews
Elisa Piedra M, Borja Rivero1 F, Fernandez-Teran M, Ros MA.
Pattern formation and regulation of gene
expressions in chick recombinant limbs.
Mech Dev. 2000 Feb
1;90(2):167-179.
[Record as supplied by publisher]
PMID: 10640702
Scaal M, Bonafede A, Dathe V, Sachs M, Cann G, Christ B, Brand-Saberi B.
SF/HGF is a mediator between limb patterning
and muscle development.
Development. 1999
Nov;126(21):4885-93.
PMID: 10518504; UI: 99449583
Expression of the Sonic hedgehog (SHH ) gene
during early human development and phenotypic
expression of new mutations causing
holoprosencephaly.
Hum Mol Genet. 1999
Sep;8(9):1683-9.
PMID: 10441331; UI: 99371775
Caruccio NC, Martinez-Lopez A, Harris M, Dvorak L, Bitgood J, Simandl BK, Fallon JF.
Constitutive activation of sonic hedgehog
signaling in the chicken mutant talpid(2):
Shh-independent outgrowth and polarizing
activity.
Dev Biol. 1999 Aug
1;212(1):137-49.
PMID: 10419691; UI: 99350224
Duprez D, Lapointe F, Edom-Vovard F, Kostakopoulou K, Robson L.
Sonic hedgehog (SHH) specifies muscle
pattern at tissue and cellular chick level, in
the chick limb bud.
Mech Dev. 1999
Apr;82(1-2):151-63.
PMID: 10354479; UI: 99284526
Fernandez-Teran M, Piedra ME, Ros MA, Fallon JF.
The recombinant limb as a model for the
study of limb patterning, and its application to
muscle development.
Cell Tissue Res. 1999
Apr;296(1):121-9. Review.
PMID: 10199972; UI: 99216345
Theil T, Kaesler S, Grotewold L, Bose J, Ruther U.
Gli genes and limb development.
Cell Tissue Res. 1999
Apr;296(1):75-83. Review.
PMID: 10199967; UI: 99216340
A mathematical model for outgrowth and
spatial patterning of the vertebrate limb
bud.
J Theor Biol. 1999 Apr
7;197(3):295-330.
PMID: 10089144; UI: 99190730
[Signaling molecules involved in
induction and early patterning of limb
buds].
Kaibogaku Zasshi. 1998
Dec;73(6):655-66. Review. Japanese.
PMID: 9990203; UI: 99144014
Fgf10 is essential for limb and lung
formation.
Nat Genet. 1999
Jan;21(1):138-41.
PMID: 9916808; UI: 99113846
Munoz-Sanjuan I, Simandl BK, Fallon JF, Nathans J.
Related Articles, Protein, Nucleotide
Expression of chicken fibroblast growth
factor homologous factor (FHF)-1 and of
differentially spliced isoforms of FHF-2 during
development and involvement of FHF-2 in chicken
limb development.
Development. 1999
Jan;126(2):409-21.
PMID: 9847253; UI: 99065510
The molecular ZPA.
J Exp Zool. 1998 Dec
15;282(6):677-90. Review.
PMID: 9846380; UI: 99062810
Expression of sonic hedgehog gene in
regenerating newt limbs.
Wound Repair Regen. 1998
Jul-Aug;6(4):366-70. Review.
PMID: 9824555; UI: 99065743
Ng JK, Tamura K, Buscher D, Izpisua-Belmonte JC.
Molecular and cellular basis of pattern
formation during vertebrate limb
development.
Curr Top Dev Biol.
1999;41:37-66. Review.
PMID: 9784972; UI: 99001151
Laforest L, Brown CW, Poleo G, Geraudie J, Tada M, Ekker M, Akimenko MA.
Involvement of the sonic hedgehog, patched 1
and bmp2 genes in patterning of the zebrafish
dermal fin rays.
Development. 1998
Nov;125(21):4175-84.
PMID: 9753672; UI: 98428602
Shh, Bmp-2 and Hoxd-13 gene expression in
chick limb bud cells in culture.
Dev Growth Differ. 1998
Aug;40(4):457-64.
PMID: 9727360; UI: 98394343
Cooperating morphogens control hoxd gene
expression in the developing vertebrate
limb.
J Theor Biol. 1998 May
7;192(1):43-53.
PMID: 9714615; UI: 98372062
Effects of FGFs on the morphogenic potency
and AER-maintenance activity of cultured
progress zone cells of chick limb bud.
Int J Dev Biol. 1998
May;42(4):591-9.
PMID: 9694630; UI: 98358006
mRNA expression patterns of the IGF system
during mouse limb bud development, determined by
whole mount in situ hybridization.
Mol Cell Endocrinol. 1998 Mar
16;138(1-2):151-61.
PMID: 9685224; UI: 98348385
Yang Y, Guillot P, Boyd Y, Lyon MF, McMahon AP.
Evidence that preaxial polydactyly in the
Doublefoot mutant is due to ectopic Indian
Hedgehog signaling.
Development. 1998
Aug;125(16):3123-32.
PMID: 9671585; UI: 98337831
Signaling during development, though complex, can also be grouped into a few specific classes. These mechanisms have also been listed and described briefly on Signaling Mechanisms page.
Lecture Notes |
Please note that these notes only relate to an earlier Course and not all Lecture notes and research material have been transferred. |
| |
Simple pictures illustrating the early events of fertilization. |
| |
Figures and text relating to early events of spinal cord formation. |
| |
Text relating to the molecular events of sex determination in the embryo. |
| |
A short comparison of establishing positional information in embryos. |
| |
The fly mutation that opened the field of Hox Genes and the conservation of pattern formation control mechanisms between species in embryonic development. |
antisense- a sequence of DNA that is complementary usually to coding sequence of DNA or mRNA. Has been used experimentally to perturb or block gene expression. Also a mechanism that has been found to occur naturally as a regulatory mechanism.
autosomal inheritance- some hereditary diseases are described as autosomal which means that the disease is due to a DNA error in one of the 22 pairs that are not sex chromosomes. Both boys and girls can then inherit this error. If the error is in a sex chromosome, the inheritance is said to be sex-linked.
base- another term for nucleotide (usually a t c g).
base pair- Double stranded DNA has nucleotides A-T, C-G, paired by hydrogen bonds (2 for AT, 3 for GC). Note this means that GC is harder to separate that AT.
DNA- DeoxyriboNucleic Acid. The genetic material found in mammalian chromosomes and mitochondria. Consisting of 4 nucleic acids (ATCG) that combine in a triptych (3 nucleotide) code for protein amino acids (3nt=1aa).
DNA duplex- double stranded base-paired DNA forming a helix.
dominant inheritance-With autosomal dominant inheritance, there is an error in one of the 22 chromosome pairs. But the damaged gene dominates over the normal gene received from the other parent. If one of the parents has a disease caused by an autosomal dominant gene, all the children will have a 50 per cent risk of inheriting the dominant gene and a 50 per cent chance of not inheriting it. The children who do not inherit the damaged dominant gene will not themselves suffer from the disease, nor will they be able to pass the gene on to future children. This type of inheritance is present for example in Huntington's disease.
exon- a block of protein encoding sequence of DNA in a gene. Many proteins are made of several exons "stitched" or spliced together by editing out non-coding (intron) sequences.
fasta- a format for listing DNA sequence, where the first line has descritive information followed on the next line by the sequence without numbering.
GC repeat- a string of GC sequence repeated several times. Also associated with GC expansion, a mutational process that may lead eventually to serious gene expression effects.
gene- a sequence of DNA that encodes an individual protein.
genetic code- the 3 nucleotide sequence that forms a codon for a single amino acid or stop. See the gene code.
genome- the complete genetic information in the form of DNA available to a specific species.
hairpin loop- a folding of RNA generated by base pairing making a "===()" structure, the end loop and or stem of this structure can then interact with proteins or other RNA.
intron- a block of DNA within a gene not encoding a protein. Edited, spliced, out during transcription into mRNA. Originally thought not to contain any information, but more and more this appears not to be the case. Some intron sequences have been shown to regulate gene expression during development (eg c elegans, Lin 14)
mRNA- messenger, transcribed from DNA in the nucleus and in mitochondria. Is translated by the ribosome in the cytoplasm (or mitochondrial matrix). Intermediate step in gene expression. (DNA-> mRNA-> protein).
mutation- any process which results in the alteration of the DNA sequence. Some conservative mutations may have no effect on the final amino acid encoded.
point mutation- a change in a single nucleotide.
recessive inheritance-With autosomal recessive inheritance, the diseased individual has inherited the same gene damage from both father and mother. The damage is found on both chromosomes in the pair. But as this is not ´dominant gene damageª, neither father nor mother show any sign of disease, they are healthy carriers of the gene. We are all carriers of about five recessive genes of this type, but as spouses are seldom carriers of exactly the same damaged gene(s), all will probably go well in the next generation.
ribosome- complex of rRNA and ribosomal proteins, bind mRNA and translate it into protein.
RNA- RiboNucleic Acid. The intermediate nucleic acid involved in gene expression. It comes in 3 forms: tRNA, mRNA, rRNA.
rRNA- ribosomal, translates mRNA into protein. rRNA provides the "scaffolding" on which many ribosomal proteins are assembled as 2 subunits that themselves assemble to form a ribosome. rRNA genes are localized to the nucleolus in the nucleus, a sometimes visible region of DNA usually constantly being transcribed.
telomere- regions at the end of chromosomes. Shortening of the telomeres is thought to be associated with cellular aging. The enzyme that maintains the telomere is called telomerase. Introducing this gene into a cell can extend the cells lifespan.
transcription factor- a protein which binds to DNA activating (usually) gene expression. There are many different ways and forms that this activation can take place, but most transcription factors fall into specific classes (eg zinc fingers, helix loop helix).
tRNA- transfer, binds single amino acids acts as a "donor' for protein synthesis.
Home Page
Embryo stages
Fetal Dev
Dev Notes 1
Dev Notes 2
System Notes
Acknowledgements
Movies
Class Notes
Serial Images
K12 Students
Abnormal
Embryology in the News
Histology
Site Map
Molecular Development
Axes Formation
Early Axis
Rostro/Caudal Axis
Anterior/Posterior Axis
Left/Right Axis
Limb Axes
School of Med Sci
UNSW Medicine
University of NSW
UNSW Cell Biology
NCBI Books
Dev Biol (Gilbert)
This section of notes introduces the topic of axes formation which establishes body patterns in multicellular organisms.
While the final animals are significantly different, the mechanisms that regulate axis formation have common molecular pathways and signals.
An excellent example is the patterning of the limb, which has been a model for axis formation.
Molecular mechanisms of development is an exciting area and requires a variety of different skills. This page introduces only a few examples and should give you a feel for the topic.
Please email Dr Mark Hill if you wish to make a comment about this current project.